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1.
J Am Soc Nephrol ; 33(3): 565-582, 2022 03.
Article in English | MEDLINE | ID: covidwho-1883777

ABSTRACT

BACKGROUND: Endothelial cell injury is a common nidus of renal injury in patients and consistent with the high prevalence of AKI reported during the coronavirus disease 2019 pandemic. This cell type expresses integrin α5 (ITGA5), which is essential to the Tie2 signaling pathway. The microRNA miR-218-5p is upregulated in endothelial progenitor cells (EPCs) after hypoxia, but microRNA regulation of Tie2 in the EPC lineage is unclear. METHODS: We isolated human kidney-derived EPCs (hkEPCs) and surveyed microRNA target transcripts. A preclinical model of ischemic kidney injury was used to evaluate the effect of hkEPCs on capillary repair. We used a genetic knockout model to evaluate the effect of deleting endogenous expression of miR-218 specifically in angioblasts. RESULTS: After ischemic in vitro preconditioning, miR-218-5p was elevated in hkEPCs. We found miR-218-5p bound to ITGA5 mRNA transcript and decreased ITGA5 protein expression. Phosphorylation of 42/44 MAPK decreased by 73.6% in hkEPCs treated with miR-218-5p. Cells supplemented with miR-218-5p downregulated ITGA5 synthesis and decreased 42/44 MAPK phosphorylation. In a CD309-Cre/miR-218-2-LoxP mammalian model (a conditional knockout mouse model designed to delete pre-miR-218-2 exclusively in CD309+ cells), homozygotes at e18.5 contained avascular glomeruli, whereas heterozygote adults showed susceptibility to kidney injury. Isolated EPCs from the mouse kidney contained high amounts of ITGA5 and showed decreased migratory capacity in three-dimensional cell culture. CONCLUSIONS: These results demonstrate the critical regulatory role of miR-218-5p in kidney EPC migration, a finding that may inform efforts to treat microvascular kidney injury via therapeutic cell delivery.


Subject(s)
Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Endothelial Progenitor Cells/metabolism , Endothelial Progenitor Cells/pathology , Integrin alpha5/metabolism , MicroRNAs/physiology , Acute Kidney Injury/pathology , Animals , Disease Models, Animal , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptor, TIE-2/physiology , Signal Transduction/physiology
2.
J Cell Mol Med ; 26(7): 1979-1993, 2022 04.
Article in English | MEDLINE | ID: covidwho-1774827

ABSTRACT

Acute kidney injury (AKI) is a substantial worldwide public health concern with no specific and effective therapies in clinic. NAD+ is a pivotal determinant of cellular energy metabolism involved in the progression of AKI; however, its mechanism in kidney injury remains poorly understood. Sirtuin 1 (SIRT1) is an NAD+ -dependent deacetylase associated with renal protection and acute stress resistance. In this study, we have investigated the role of NAD+ in AKI and the potential mechanism(s) involved in its renoprotective effect. NAD+ was notably decreased and negatively correlated with kidney dysfunction in AKI, restoring NAD+ with NMN significantly ameliorates LPS-induced oxidative stress and apoptosis and attenuates renal damage. We also found that the protection of NAD+ is associated with SIRT1 expressions and performs in a SIRT1-dependent manner. Inhibition of SIRT1 blunted the protective effect of NAD+ and up-regulated the activity of glycogen synthase kinase-3ß (GSK-3ß) that was concomitant with mitigated Nrf2 nuclear accumulation, thereby exacerbates AKI. These findings suggest that NAD+ /SIRT1/GSK-3ß/Nrf2 axis is an important mechanism that can protect against AKI which might be a potential therapeutic target for the treatment of AKI.


Subject(s)
Acute Kidney Injury , Glycogen Synthase Kinase 3 beta , NAD , NF-E2-Related Factor 2 , Sirtuin 1 , Acute Kidney Injury/metabolism , Endotoxins , Glycogen Synthase Kinase 3 beta/metabolism , Humans , NAD/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Sirtuin 1/genetics , Sirtuin 1/metabolism
3.
Int J Infect Dis ; 117: 302-311, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1693388

ABSTRACT

BACKGROUND: Acute renal injury is an important complication of coronavirus disease 2019 (COVID-19). Both COVID-19-specific mechanisms, such as damage to the renal parenchyma by direct infection, and non-specific mechanisms, such as the pre-renal injury factors, have been proposed to be involved in COVID-19-associated renal injuries. In this study, we aimed to elucidate the characteristics of COVID-19-associated renal injuries, focusing mainly on urine sediment findings. METHODS: We compared the urine sediment findings and their associations with renal functions or urinary clinical parameters between subjects with COVID-19 and subjects without COVID-19 with acute renal injuries. RESULTS: We found that the number of urine sediment particles and the levels of N-acetyl-ß-D-glucosaminidase, α1-microglobulin, liver type fatty acid-binding protein, and neutrophil gelatinase-associated lipocalin were associated with the severity of COVID-19. In addition, we observed that the number of granular casts, epithelial casts, waxy casts, and urinary chemical marker levels were lower in the subjects with COVID-19 than subjects without COVID-19 with acute renal injuries when the subjects were classified according to their renal function. CONCLUSIONS: These results suggest that pre-renal injury factors might be largely involved in the pathogenesis of COVID-19-associated renal injuries compared with non-COVID-19-associated renal injuries arising from surgery or sepsis.


Subject(s)
Acute Kidney Injury , COVID-19 , Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Biomarkers/urine , COVID-19/complications , Humans , Kidney/metabolism , Urinalysis/adverse effects
4.
Acta Biochim Biophys Sin (Shanghai) ; 54(1): 1-11, 2022 01 25.
Article in English | MEDLINE | ID: covidwho-1674885

ABSTRACT

Since the first reported case in December of 2019, the coronavirus disease 2019 (COVID-19) has became an international public health emergency. So far, there are more than 228,206,384 confirmed cases including 4,687,066 deaths. Kidney with high expression of angiotensin-converting enzyme 2 (ACE2) is one of the extrapulmonary target organs affected in patients with COVID-19. Acute kidney injury (AKI) is one of the independent risk factors for the death of COVID-19 patients. The imbalance between ACE2-Ang(1-7)-MasR and ACE-Ang II-AT1R axis in the kidney may contribute to COVID-19-associated AKI. Although series of research have shown the inconsistent effects of multiple common RAS inhibitors on ACE2 expression and enzyme activity, most of the retrospective cohort studies indicated the safety and protective effects of ACEI/ARB in COVID-19 patients. This review article highlights the current knowledge on the possible involvement of intrarenal RAS in COVID-19-associated AKI with a primary focus on the opposing effects of ACE2-Ang(1-7)-MasR and ACE-Ang II-AT1R signaling in the kidney. Human recombinant soluble ACE2 or ACE2 variants with preserved ACE2-enzymatic activity may be the best options to improve COVID-19-associated AKI.


Subject(s)
Acute Kidney Injury/etiology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/complications , Kidney/physiology , Renin-Angiotensin System/physiology , SARS-CoV-2/pathogenicity , Acute Kidney Injury/drug therapy , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Animals , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Humans , Kidney/drug effects , Renin-Angiotensin System/drug effects , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism
5.
Adv Sci (Weinh) ; 9(3): e2103248, 2022 01.
Article in English | MEDLINE | ID: covidwho-1527412

ABSTRACT

COVID-19 is infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and can cause severe multiple organ injury and death. Kidney is one of major target organs of COVID-19 and acute kidney injury (AKI) is common in critically ill COVID-19 patients. However, mechanisms through which COVID-19 causes AKI remain largely unknown and treatment remains unspecific and ineffective. Here, the authors report that normal kidney-specifically overexpressing SARS-CoV-2 N develops AKI, which worsens in mice under ischemic condition. Mechanistically, it is uncovered that SARS-CoV-2 N-induced AKI is Smad3-dependent as SARS-CoV-2 N protein can interact with Smad3 and enhance TGF-ß/Smad3 signaling to cause tubular epithelial cell death and AKI via the G1 cell cycle arrest mechanism. This is further confirmed in Smad3 knockout mice and cells in which deletion of Smad3 protects against SARS-CoV-2 N protein-induced cell death and AKI in vivo and in vitro. Most significantly, it is also found that targeting Smad3 with a Smad3 pharmacological inhibitor is able to inhibit SARS-CoV-2 N-induced AKI. In conclusion, the authors identify that SARS-CoV-2 N protein is a key mediator for AKI and induces AKI via the Smad3-dependent G1 cell cycle arrest mechanism. Targeting Smad3 may represent as a novel therapy for COVID-19-asscoaited AKI.


Subject(s)
Acute Kidney Injury , COVID-19 , Coronavirus Nucleocapsid Proteins , G1 Phase Cell Cycle Checkpoints , SARS-CoV-2 , Smad3 Protein , Acute Kidney Injury/genetics , Acute Kidney Injury/metabolism , Acute Kidney Injury/virology , Animals , COVID-19/genetics , COVID-19/metabolism , Cell Line , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/metabolism , Disease Models, Animal , HEK293 Cells , Humans , Mice , Mice, Knockout , Phosphoproteins/genetics , Phosphoproteins/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Smad3 Protein/genetics , Smad3 Protein/metabolism
6.
Int J Mol Sci ; 22(12)2021 Jun 20.
Article in English | MEDLINE | ID: covidwho-1472414

ABSTRACT

Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients. Current treatments are limited to slowing instead of stabilising or reversing disease progression. In this review, we describe mesenchymal stem cells (MSCs) and their constituents, extracellular vesicles (EVs) as being a novel therapeutic for CKD. MSC-derived EVs (MSC-EVs) are membrane-enclosed particles, including exosomes, which carry genetic information that mimics the phenotype of their cell of origin. MSC-EVs deliver their cargo of mRNA, miRNA, cytokines, and growth factors to target cells as a form of paracrine communication. This genetically reprograms pathophysiological pathways, which are upregulated in renal failure. Since the method of exosome preparation significantly affects the quality and function of MSC-exosomes, this review compares the methodologies for isolating exosomes from MSCs and their role in tissue regeneration. More specifically, it summarises the therapeutic efficacy of MSC-EVs in 60 preclinical animal models of AKI and CKD and the cargo of biomolecules they deliver. MSC-EVs promote tubular proliferation and angiogenesis, and inhibit apoptosis, oxidative stress, inflammation, the epithelial-to-mesenchymal transition, and fibrosis, to alleviate AKI and CKD. By reprogramming these pathophysiological pathways, MSC-EVs can slow or even reverse the progression of AKI to CKD, and therefore offer potential to transform clinical practice.


Subject(s)
Biological Therapy , Extracellular Vesicles/metabolism , Extracellular Vesicles/transplantation , Kidney Diseases/therapy , Mesenchymal Stem Cells/metabolism , Acute Kidney Injury/diagnosis , Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Acute Kidney Injury/therapy , Animals , Apoptosis/drug effects , Biological Therapy/methods , Cell Differentiation , Cell Proliferation/drug effects , Cell Self Renewal , Chemical Fractionation , Disease Management , Disease Susceptibility , Exosomes/metabolism , Humans , Kidney Diseases/etiology , Kidney Diseases/pathology , Mesenchymal Stem Cells/cytology , Protective Agents , Renal Insufficiency/diagnosis , Renal Insufficiency/etiology , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/therapy
7.
PLoS One ; 16(9): e0257253, 2021.
Article in English | MEDLINE | ID: covidwho-1443836

ABSTRACT

OBJECTIVES: Studies have shown that acute kidney injury (AKI) occurrence post SARS-CoV-2 infection is complex and has a poor prognosis. Therefore, more studies are needed to understand the rate and the predications of AKI involvement among hospitalized COVID-19 patients and AKI's impact on prognosis while under different types of medications. PATIENTS AND METHODS: This study is a retrospective observational cohort study conducted at Bahrain Defence Force (BDF) Royal Medical Services. Medical records of COVID-19 patients admitted to BDF hospital, treated, and followed up from April 2020 to October 2020 were retrieved. Data were analyzed using univariate and multivariate logistic regression with covariate adjustment, and the odds ratio (OR) and 95% confidence (95% CI) interval were reported. RESULTS: Among 353 patients admitted with COVID-19, 47.6% developed AKI. Overall, 51.8% of patients with AKI died compared to 2.2% of patients who did not develop AKI (p< 0.001 with OR 48.6 and 95% CI 17.2-136.9). Besides, deaths in patients classified with AKI staging were positively correlated and multivariate regression analysis revealed that moderate to severe hypoalbuminemia (<32 g/L) was independently correlated to death in AKI patients with an OR of 10.99 (CI 95% 4.1-29.3, p<0.001). In addition, 78.2% of the dead patients were on mechanical ventilation. Besides age as a predictor of AKI development, diabetes and hypertension were the major risk factors of AKI development (OR 2.04, p<0.01, and 0.05 for diabetes and hypertension, respectively). Also, two or more comorbidities substantially increased the risk of AKI development in COVID-19 patients. Furthermore, high levels upon hospital admission of D-Dimer, Troponin I, and ProBNP and low serum albumin were associated with AKI development. Lastly, patients taking ACEI/ARBs had less chance to develop AKI stage II/III with OR of 0.19-0.27 (p<0.05-0.01). CONCLUSIONS: The incidence of AKI in hospitalized COVID-19 patients and the mortality rate among AKI patients were high and correlated with AKI staging. Furthermore, laboratory testing for serum albumin, hypercoagulability and cardiac injury markers maybe indicative for AKI development. Therefore, clinicians should be mandated to perform such tests on admission and follow-up in hospitalized patients.


Subject(s)
Acute Kidney Injury/epidemiology , COVID-19/complications , Acute Kidney Injury/metabolism , Acute Kidney Injury/physiopathology , Adult , Aged , Bahrain/epidemiology , COVID-19/physiopathology , Cohort Studies , Comorbidity , Female , Hospital Mortality , Hospitalization/trends , Hospitals , Humans , Incidence , Intensive Care Units , Male , Middle Aged , Prognosis , Respiration, Artificial/adverse effects , Retrospective Studies , Risk Factors , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity
8.
Adv Sci (Weinh) ; 8(18): e2101498, 2021 09.
Article in English | MEDLINE | ID: covidwho-1316192

ABSTRACT

Acute kidney injury (AKI), as a common oxidative stress-related renal disease, causes high mortality in clinics annually, and many other clinical diseases, including the pandemic COVID-19, have a high potential to cause AKI, yet only rehydration, renal dialysis, and other supportive therapies are available for AKI in the clinics. Nanotechnology-mediated antioxidant therapy represents a promising therapeutic strategy for AKI treatment. However, current enzyme-mimicking nanoantioxidants show poor biocompatibility and biodegradability, as well as non-specific ROS level regulation, further potentially causing deleterious adverse effects. Herein, the authors report a novel non-enzymatic antioxidant strategy based on ultrathin Ti3 C2 -PVP nanosheets (TPNS) with excellent biocompatibility and great chemical reactivity toward multiple ROS for AKI treatment. These TPNS nanosheets exhibit enzyme/ROS-triggered biodegradability and broad-spectrum ROS scavenging ability through the readily occurring redox reaction between Ti3 C2 and various ROS, as verified by theoretical calculations. Furthermore, both in vivo and in vitro experiments demonstrate that TPNS can serve as efficient antioxidant platforms to scavenge the overexpressed ROS and subsequently suppress oxidative stress-induced inflammatory response through inhibition of NF-κB signal pathway for AKI treatment. This study highlights a new type of therapeutic agent, that is, the redox-mediated non-enzymatic antioxidant MXene nanoplatforms in treatment of AKI and other ROS-associated diseases.


Subject(s)
Acute Kidney Injury/drug therapy , Antioxidants/pharmacology , Oxidation-Reduction/drug effects , Polyvinyls/pharmacology , Pyrrolidines/pharmacology , Titanium/pharmacology , Acute Kidney Injury/metabolism , Apoptosis/drug effects , Humans , Kidney/drug effects , Kidney/metabolism , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects
9.
Ther Drug Monit ; 43(4): 455-458, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1305444

ABSTRACT

ABSTRACT: In this article, we present a case of apixaban elimination prolonged by 450% in a patient with coronavirus disease 2019 because of multiple conditions, including drug-drug interaction, severe inflammation, and acute kidney injury. Therapeutic drug monitoring was used to explain unusual routine coagulation assays. This grand round highlights the importance of dialog between the clinician and a therapeutic drug monitoring consultant for optimal patient care.


Subject(s)
Acute Kidney Injury/metabolism , COVID-19/metabolism , Drug Monitoring/methods , Pyrazoles/metabolism , Pyridones/metabolism , Renal Elimination/drug effects , Teaching Rounds/methods , Acute Kidney Injury/chemically induced , Acute Kidney Injury/prevention & control , Aged, 80 and over , Antiviral Agents/adverse effects , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Interactions/physiology , Factor Xa Inhibitors/adverse effects , Factor Xa Inhibitors/metabolism , Factor Xa Inhibitors/therapeutic use , Humans , Inflammation/chemically induced , Inflammation/metabolism , Inflammation/prevention & control , Male , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Pyridones/adverse effects , Pyridones/therapeutic use , Renal Elimination/physiology , Severity of Illness Index , Time Factors
10.
Nano Lett ; 21(10): 4394-4402, 2021 05 26.
Article in English | MEDLINE | ID: covidwho-1230861

ABSTRACT

The high demand for acute kidney injury (AKI) therapy calls the development of multifunctional nanomedicine for renal management with programmable pharmacokinetics. Here, we developed a renal-accumulating DNA nanodevice with exclusive kidney retention for longitudinal protection of AKI in different stages in a renal ischemia-reperfusion (I/R) model. Due to the prolonged kidney retention time (>12 h), the ROS-sensitive nucleic acids of the nanodevice could effectively alleviate oxidative stress by scavenging ROS in stage I, and then the anticomplement component 5a (aC5a) aptamer loaded nanodevice could sequentially suppress the inflammatory responses by blocking C5a in stage II, which is directly related to the cytokine storm. This sequential therapy provides durable and pathogenic treatment of kidney dysfunction based on successive pathophysiological events induced by I/R, which holds great promise for renal management and the suppression of the cytokine storm in more broad settings including COVID-19.


Subject(s)
Acute Kidney Injury , COVID-19 , Reperfusion Injury , Acute Kidney Injury/drug therapy , Acute Kidney Injury/metabolism , Humans , Kidney/metabolism , Oxidative Stress , Reperfusion Injury/drug therapy , SARS-CoV-2
11.
Ther Drug Monit ; 43(4): 455-458, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1205884

ABSTRACT

ABSTRACT: In this article, we present a case of apixaban elimination prolonged by 450% in a patient with coronavirus disease 2019 because of multiple conditions, including drug-drug interaction, severe inflammation, and acute kidney injury. Therapeutic drug monitoring was used to explain unusual routine coagulation assays. This grand round highlights the importance of dialog between the clinician and a therapeutic drug monitoring consultant for optimal patient care.


Subject(s)
Acute Kidney Injury/metabolism , COVID-19/metabolism , Drug Monitoring/methods , Pyrazoles/metabolism , Pyridones/metabolism , Renal Elimination/drug effects , Teaching Rounds/methods , Acute Kidney Injury/chemically induced , Acute Kidney Injury/prevention & control , Aged, 80 and over , Antiviral Agents/adverse effects , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Interactions/physiology , Factor Xa Inhibitors/adverse effects , Factor Xa Inhibitors/metabolism , Factor Xa Inhibitors/therapeutic use , Humans , Inflammation/chemically induced , Inflammation/metabolism , Inflammation/prevention & control , Male , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Pyridones/adverse effects , Pyridones/therapeutic use , Renal Elimination/physiology , Severity of Illness Index , Time Factors
12.
Physiol Genomics ; 53(6): 249-258, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1186377

ABSTRACT

A worldwide coronavirus pandemic is in full swing and, at the time of writing, there are only few treatments that have been successful in clinical trials, but no effective antiviral treatment has been approved. Because of its lethality, it is important to understand the current strain's effects and mechanisms not only in the respiratory system but also in other affected organ systems as well. Past coronavirus outbreaks caused by SARS-CoV and MERS-CoV inflicted life-threatening acute kidney injuries (AKI) on their hosts leading to significant mortality rates, which went somewhat overlooked in the face of the severe respiratory effects. Recent evidence has emphasized renal involvement in SARS-CoV-2, stressing that kidneys are damaged in patients with COVID-19. The mechanism by which this virus inflicts AKI is still unclear, but evidence from other coronavirus strains may hold some clues. Two theories exist for the proposed mechanism of AKI: 1) the AKI is a secondary effect to reduced blood and oxygen levels causing hyperinflammation and 2) the AKI is due to cytotoxic effects. Kidneys express angiotensin-converting enzyme-2 (ACE2), the confirmed SARS-CoV-2 target receptor as well as collectrin, an ACE2 homologue that localizes to the primary cilium, an organelle historically targeted by coronaviruses. Although the available literature suggests that kidney damage is leading to higher mortality rates in patients with COVID-19, especially in those with preexisting kidney and cardiovascular diseases, the pathogenesis of COVID-19 is still being investigated. Here, we present brief literature review supporting our proposed hypothesis of a possible link between SARS-CoV-2 cellular infection and cilia.


Subject(s)
Acute Kidney Injury/virology , COVID-19/virology , Cilia/virology , Kidney/virology , SARS-CoV-2/pathogenicity , Virus Internalization , Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/complications , Cilia/metabolism , Cilia/pathology , Host-Pathogen Interactions , Humans , Kidney/metabolism , Kidney/pathology
13.
JAMA Netw Open ; 4(3): e211095, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1125117

ABSTRACT

Importance: Acute kidney injury (AKI) occurs in up to half of patients hospitalized with coronavirus disease 2019 (COVID-19). The longitudinal effects of COVID-19-associated AKI on kidney function remain unknown. Objective: To compare the rate of change in estimated glomerular filtration rate (eGFR) after hospital discharge between patients with and without COVID-19 who experienced in-hospital AKI. Design, Setting, and Participants: A retrospective cohort study was conducted at 5 hospitals in Connecticut and Rhode Island from March 10 to August 31, 2020. Patients who were tested for COVID-19 and developed AKI were screened, and those who survived past discharge, did not require dialysis within 3 days of discharge, and had at least 1 outpatient creatinine level measurement following discharge were included. Exposures: Diagnosis of COVID-19. Main Outcomes and Measures: Mixed-effects models were used to assess the association between COVID-19-associated AKI and eGFR slope after discharge. The secondary outcome was the time to AKI recovery for the subgroup of patients whose kidney function had not returned to the baseline level by discharge. Results: A total of 182 patients with COVID-19-associated AKI and 1430 patients with AKI not associated with COVID-19 were included. The population included 813 women (50.4%); median age was 69.7 years (interquartile range, 58.9-78.9 years). Patients with COVID-19-associated AKI were more likely to be Black (73 [40.1%] vs 225 [15.7%]) or Hispanic (40 [22%] vs 126 [8.8%]) and had fewer comorbidities than those without COVID-19 but similar rates of preexisting chronic kidney disease and hypertension. Patients with COVID-19-associated AKI had a greater decrease in eGFR in the unadjusted model (-11.3; 95% CI, -22.1 to -0.4 mL/min/1.73 m2/y; P = .04) and after adjusting for baseline comorbidities (-12.4; 95% CI, -23.7 to -1.2 mL/min/1.73 m2/y; P = .03). In the fully adjusted model controlling for comorbidities, peak creatinine level, and in-hospital dialysis requirement, the eGFR slope difference persisted (-14.0; 95% CI, -25.1 to -2.9 mL/min/1.73 m2/y; P = .01). In the subgroup of patients who had not achieved AKI recovery by discharge (n = 319), COVID-19-associated AKI was associated with decreased kidney recovery during outpatient follow-up (adjusted hazard ratio, 0.57; 95% CI, 0.35-0.92). Conclusions and Relevance: In this cohort study of US patients who experienced in-hospital AKI, COVID-19-associated AKI was associated with a greater rate of eGFR decrease after discharge compared with AKI in patients without COVID-19, independent of underlying comorbidities or AKI severity. This eGFR trajectory may reinforce the importance of monitoring kidney function after AKI and studying interventions to limit kidney disease after COVID-19-associated AKI.


Subject(s)
Acute Kidney Injury/metabolism , COVID-19/metabolism , Creatinine/metabolism , Acute Kidney Injury/complications , Acute Kidney Injury/epidemiology , African Americans , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/epidemiology , Cohort Studies , Comorbidity , Female , Follow-Up Studies , Glomerular Filtration Rate , Humans , Hypertension/epidemiology , Kidney Function Tests , Longitudinal Studies , Male , Middle Aged , Patient Discharge , Proportional Hazards Models , Renal Insufficiency, Chronic/epidemiology , Retrospective Studies , SARS-CoV-2 , United States/epidemiology
14.
Am J Physiol Renal Physiol ; 320(2): F243-F248, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1035216

ABSTRACT

Coronavirus disease 2019 (COVID-19) has reached pandemic proportions, affecting millions of people worldwide. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19. Epidemiological reports have shown that the severity of SARS-CoV-2 infection is associated with preexisting comorbidities such as hypertension, diabetes mellitus, cardiovascular diseases, and chronic kidney diseases, all of which are also risk factors for acute kidney injury (AKI). The kidney has emerged as a key organ affected by SARS-CoV-2. AKI is associated with increased morbidity and mortality in patients with COVID-19. Male sex is an independent predictor for AKI, and an increased death rate has been reported in male patients with COVID-19 worldwide. The mechanism(s) that mediate the sex discrepancy in mortality due to COVID-19 remain(s) unknown. Angiotensin-converting enzyme (ACE)2 is the receptor for SARS-CoV-2. Alterations in the ACE-to-ACE2 ratio have been implicated in renal diseases. This perspective aims to discuss data that suggest that androgens, via alterations in the intrarenal renin-angiotensin system, impair renal hemodynamics, predisposing patients to AKI during COVID-19 infection, which could explain the higher mortality observed in men with COVID-19. Clinicians should ensure early and effective cardiometabolic control for all patients to ameliorate the compensatory elevation of ACE2 and alterations in the ACE-to-ACE2 ratio. A better understanding of the role of androgens in SARS-CoV-2-associated AKI and mortality is imperative. The kidney could constitute a key organ that may explain the sex disparities of the higher mortality and worst outcomes associated with COVID-19 in men.


Subject(s)
Acute Kidney Injury/virology , Androgens/metabolism , COVID-19/mortality , COVID-19/pathology , Kidney/metabolism , SARS-CoV-2 , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Angiotensin-Converting Enzyme 2/metabolism , Female , Gene Expression Regulation , Humans , Male , Polycystic Ovary Syndrome , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Sex Factors , Transgender Persons
15.
Adv Chronic Kidney Dis ; 27(5): 365-376, 2020 09.
Article in English | MEDLINE | ID: covidwho-975047

ABSTRACT

Acute kidney injury (AKI) is common among hospitalized patients with Coronavirus Infectious Disease 2019 (COVID-19), with the occurrence of AKI ranging from 0.5% to 80%. The variability in the occurrence of AKI has been attributed to the difference in geographic locations, race/ethnicity, and severity of illness. AKI among hospitalized patients is associated with increased length of stay and in-hospital deaths. Even patients with AKI who survive to hospital discharge are at risk of developing chronic kidney disease or end-stage kidney disease. An improved knowledge of the pathophysiology of AKI in COVID-19 is crucial to mitigate and manage AKI and to improve the survival of patients who developed AKI during COVID-19. The goal of this article is to provide our current understanding of the etiology and the pathophysiology of AKI in the setting of COVID-19.


Subject(s)
Acute Kidney Injury/metabolism , COVID-19/metabolism , Cytokines/metabolism , Glomerulonephritis/metabolism , Thrombotic Microangiopathies/metabolism , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Acute Kidney Injury/physiopathology , Anti-Bacterial Agents/adverse effects , Antiviral Agents/adverse effects , Apolipoprotein L1/genetics , Ascorbic Acid/adverse effects , Azotemia/metabolism , Azotemia/pathology , Azotemia/physiopathology , COVID-19/drug therapy , COVID-19/pathology , COVID-19/physiopathology , Disease Progression , Glomerulonephritis/pathology , Glomerulonephritis/physiopathology , Glomerulonephritis, Membranous/metabolism , Glomerulonephritis, Membranous/pathology , Glomerulonephritis, Membranous/physiopathology , Hospital Mortality , Humans , Kidney Tubules, Proximal/injuries , Length of Stay , Myoglobin/metabolism , Nephritis, Interstitial/metabolism , Nephritis, Interstitial/pathology , Nephritis, Interstitial/physiopathology , Nephrosis, Lipoid/metabolism , Nephrosis, Lipoid/pathology , Nephrosis, Lipoid/physiopathology , Renal Insufficiency, Chronic , Rhabdomyolysis/metabolism , SARS-CoV-2 , Severity of Illness Index , Thrombotic Microangiopathies/pathology , Thrombotic Microangiopathies/physiopathology , Vitamins/adverse effects
16.
Ultrastruct Pathol ; 44(4-6): 519-523, 2020 Nov 20.
Article in English | MEDLINE | ID: covidwho-960391

ABSTRACT

COVID-19 (from SARS-CoV-2) is the cause of an ongoing pandemic, with an increasing number of cases and significant mortality worldwide. Clinical trials and extensive studies are being conducted on a large scale for a better understanding of the pathophysiology of this disease and its effect on different organs. Several experimental treatment protocols have been introduced, in which hydroxychloroquine (HCQ) was one of the first drugs used. While patients can develop many side effects of HCQ, studies have documented a rare association of long-term HCQ treatment with zebra-like bodies in the ultrastructural examination of kidney biopsies, a finding typically seen in Fabry's disease, as well as in association with chronic HCQ use, among other drugs. We present a similar finding in the postmortem examination of a male in his early seventies with COVID-19 infection, who received five days of HCQ treatment before stopping the medication due to cardiac and renal toxicity.


Subject(s)
Acute Kidney Injury/chemically induced , Antiviral Agents/adverse effects , COVID-19/drug therapy , Hydroxychloroquine/adverse effects , Kidney Tubules/drug effects , Organelles/drug effects , Phospholipids/metabolism , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Aged , Autopsy , Fatal Outcome , Humans , Kidney Tubules/metabolism , Kidney Tubules/ultrastructure , Male , Organelles/metabolism , Organelles/ultrastructure
17.
Aging (Albany NY) ; 13(8): 10821-10832, 2020 11 21.
Article in English | MEDLINE | ID: covidwho-946449

ABSTRACT

BACKGROUND: Novel Coronavirus disease 2019 (COVID-19) was first detected in pneumonia patients in Wuhan, China in December 2019. Based on the current understanding, COVID-19 has become a global issue. Presumably, numerous studies have found that SARS-CoV-2 also transpires in kidney tissue with permanent viral loads. However, it is elusive as to whether SARS-CoV-2 can directly damage the kidney or induce acute renal failure. Hence, to comprehensively understand the impact of COVID-19 on kidney damage, we conducted a retrospective series of case studies to assess kidney functions. Additionally, ACE2 distribution in kidney tissue was analyzed through RNAseq data in open-access databases. RESULTS: According to the findings from transcriptome analysis, we revealed higher ACE2 expression levels in females than males. Similar results were more noticeable in the elderly than in young adults. Furthermore, single-cell RNA sequencing data analysis showed high ACE2 expression in kidney tubule and collecting duct principal cells as well as glomerular parietal epithelial cells. On their admission, the patient's serum creatinine and blood urea nitrogen (BUN) were elevated to between 36.13% and 16.80%, respectively. The estimated glomerular filtration rate (EGFR) of < 60 ml/min per 1.73 m2 was reported in 10.92 % of the patients. Notably, at admission, increased BUN time varied linearly following the generalized additive mixed model. Thus, the hourly-increase of BUN in patients was 0.495 (95%CI: 0.263, 0.726). CONCLUSION: Based on clinical findings, it was ascertained that COVID-19 can damage renal function, but it seldom causes acute renal failure. Coronavirus may directly bind to ACE2-positive cells and damage kidney tissue in the analysis of scRNA-seq data in kidney tissue. Therefore, this evidence suggests that kidney tissue act as the SARS-CoV-2 infection site and the findings could provide insight into the pathophysiology of kidney damage. METHODS: We systematically analyzed ACE2 expression profiles in organs based on open-access datasets for healthy individuals. Meanwhile, single-cell sequencing data for kidney samples were collected and analyzed. Assessments on kidney functions were conducted on 119 selected COVID-19 positive patients admitted from 10th February - 18th March 2020, in hospital in Wuhan City, Hubei Province. Consequently, their clinical records and laboratory findings, such as the estimated glomerular filtration rate (eGFR), Blood Urea Nitrogen (BUN), Creatinine, and Comorbidities, were collected.


Subject(s)
Acute Kidney Injury , Angiotensin-Converting Enzyme 2 , COVID-19 , Transcriptome/genetics , Acute Kidney Injury/genetics , Acute Kidney Injury/metabolism , Acute Kidney Injury/virology , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/genetics , COVID-19/metabolism , Databases, Genetic , Female , Humans , Kidney/metabolism , Male , Middle Aged , SARS-CoV-2 , Young Adult
18.
Int Urol Nephrol ; 53(1): 97-104, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-680208

ABSTRACT

On December 30th 2019, some patients with pneumonia of unknown etiology were reported in the Program for Monitoring Emerging Diseases (ProMED), a program run by the International Society for Infectious Diseases (ISID), hypothesized to be related to subjects who had had contact with the seafood market in Wuhan, China. Chinese authorities instituted an emergency agency aimed at identifying the source of infection and potential biological pathogens. It was subsequently named by the World Committee on Virus Classification as 2019-nCoV (2019-novel coronavirus) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of studies have demonstrated that 2019-nCoV and the SARS-CoV shared the same cell entry receptor named angiotensin-converting enzyme 2 (ACE2). This is expressed in human tissues, not only in the respiratory epithelia, but also in the small intestines, heart, liver, and kidneys. Here, we examine the most recent findings on the effects of SARS-CoV-2 infection on kidney diseases, mainly acute kidney injury, and the potential role of the chemokine network.


Subject(s)
Acute Kidney Injury/etiology , COVID-19/epidemiology , Chemokines/metabolism , Kidney/metabolism , Pandemics , SARS-CoV-2 , Acute Kidney Injury/metabolism , COVID-19/complications , COVID-19/metabolism , Humans , Prognosis
19.
Anaesth Crit Care Pain Med ; 39(4): 453-455, 2020 08.
Article in English | MEDLINE | ID: covidwho-603939

ABSTRACT

The pathophysiology of acute kidney injury (AKI) in COVID-19 patients is still poorly understood. SARS-CoV-2 has been suggested to modulate the renin-angiotensin-aldosterone system (RAAS). In this series of COVID-19 critically ill patients, we report evidence of activation of the RAAS in COVID-19 patients with AKI.


Subject(s)
Acute Kidney Injury/metabolism , Betacoronavirus , Coronavirus Infections/metabolism , Pneumonia, Viral/metabolism , Renin-Angiotensin System/physiology , Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , Aged , Aldosterone/blood , COVID-19 , Coronavirus Infections/complications , Creatinine/blood , Critical Illness , Female , Humans , Intensive Care Units , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , SARS-CoV-2
20.
Eur Urol Focus ; 6(5): 1086-1096, 2020 Sep 15.
Article in English | MEDLINE | ID: covidwho-591878

ABSTRACT

CONTEXT: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that erupted in December 2019 has affected more than a million people from over 200 countries, claiming over 70 000 lives (by April 7, 2020). As the viral infection is driven by increased angiotensin-converting enzyme-2 (ACE2) expression, with the kidney exhibiting the highest expression, it is crucial to gain insights into the mechanisms underlying renal cell carcinoma (RCC) and coronavirus disease 2019 (COVID-19). OBJECTIVE: This study considers up-to-date information on the biological determinants shared by COVID-19 and renal disease, and aims to provide evidence-based recommendations for the clinical management of RCC patients with COVID-19. EVIDENCE ACQUISITION: A literature search was performed using all sources (MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, and Web of Science). As of March 31, 2020, the Center for Disease Control reported that of the adults hospitalized for COVID-19 with underlying conditions in the USA, 74.8% had chronic renal disease. EVIDENCE SYNTHESIS: Evidence is discussed from epidemiological studies on SARS-CoV-2 pandemic and molecular studies on the role of kidney in facilitating routes for SARS-CoV-2 entry, leading to increased virulence of SARS-CoV-2 and clinical manifestation of symptoms in RCC. CONCLUSIONS: This analysis will advance our understanding of (1) the molecular signatures shared by RCC and COVID-19 and (2) the clinical implications of overlapping signaling pathways in the therapeutic management of RCC and COVID-19 patients. PATIENT SUMMARY: Amid the coronavirus disease 2019 (COVID-19) pandemic, patients diagnosed with renal cell carcinoma and infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may receive complimentary treatment modalities to enhance therapeutic response.


Subject(s)
Betacoronavirus/metabolism , Carcinoma, Renal Cell/metabolism , Coronavirus Infections/metabolism , Kidney Neoplasms/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Renal Insufficiency, Chronic/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Acute Kidney Injury/epidemiology , Acute Kidney Injury/metabolism , Acute Kidney Injury/therapy , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Antiviral Agents/therapeutic use , COVID-19 , Carcinoma, Renal Cell/epidemiology , Comorbidity , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Endothelin Receptor Antagonists/therapeutic use , Hospitalization , Humans , Ipilimumab/therapeutic use , Kidney Neoplasms/drug therapy , Kidney Neoplasms/epidemiology , Liquid Biopsy , Nivolumab/therapeutic use , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Protein Kinase Inhibitors/therapeutic use , Renal Dialysis , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/therapy , SARS-CoV-2 , Serine Endopeptidases/metabolism , Severity of Illness Index , Sunitinib/therapeutic use
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